There is increasing evidence that many human cancers, including breast cancer, are driven and maintained by a cellular subcomponent that displays stem cell properties. These cancer stem cells may also mediate tumor metastasis and contribute to treatment resistance and relapse. Our laboratory has identified cellular markers and developed in vitro and mouse models to isolate and characterize normal and malignant human mammary stem cells. We have provided evidence that both hereditary and sporadic breast cancers may be initiated and maintained by dysregulation of pathways that regulate stem cell self-renewal. Furthermore, we have generated preliminary evidence that these cell intrinsic pathways may be modulated by extrinsic factors generated by components of the tumor microenvironment. These factors include a chemokine network which normally functions in tissue inflammation and repair. We propose to test the hypothesis that mammary stromal fibroblasts and mesenchymal stem cells recruited from the bone marrow regulate the self-renewal of normal and malignant breast stem cells. Furthermore, chemokine networks such as the IL-8/CXCR1 axis mediate reciprocal interactions between breast stem cells and their microenvironment. This suggests an important mechanistic link between inflammation and carcinogenesis occurs at the level of chemokine mediated stem cell regulation. We propose to develop a strategy aimed at interfering with interactions between tumor stem cells and other cells in the tumor microenvironment which comprise the stem cell niche. We will target cancer stem cells through specific blockade of the IL-8/CXCR1 axis utilizing small molecule inhibitors such as repertaxin. Since cancer stem cells may drive tumorigenesis and metastasis as well as contribute to treatment resistance and relapse, the development of novel strategies to target this cell population may lead to improved outcomes for women with advanced breast cancer.